Abstract

In chapter one, the various methods of generating benzenoid orthoquinodimethanes are discussed and approaches to their heterocyclic analogues are also reviewed. The utility of ortho-quinodimethanes in organic synthesis is highlighted by examples of both inter- and intramolecular Diels-Alder cycloadditions as the key steps in the total synthesis of naturally occurring polycyclic systems.

In chapter two, work aimed at the development of a rapid synthetic entry to heterocyclic quinodimethanes starting from ortho-methyl heterocyclic carboxylic acids is presented. To this end, the dianion of 3-methylbenzofuran-2-carboxylic acid (018) was used to facilitate the construction of a "benzylsilane type" precursor (038) which in turn when treated with fluoride base, resulted in the generation of benzofuran-2,3-quinodimethane (012). We were then successful in trapping this intermediate with reactive dienophiles to form a series of the corresponding tetrahydrodibenzofurans (042 to 049). We have been able, for the first time, to determine the regioselectivity in this reaction by performing an X-ray crystallographic analysis on the major isomer (046) arising from cyclization with methylvinylketone. Preliminary work on an intramolecular variant as well as other heterocyclic acids is also presented.

Chapter three, deals with the extensive modern approaches to tetrahydrofurans, but concentrates on examples that exhibit 2,5-disubstitution. It is sub-divided into the methods which involve an electrophile induced cyclization and the numerous alternative ones which do not. Their relevance in Natural Product assembly, especially the polyether antibiotics, is appraised.

Chapter four continues with studies which have already established that Z-3-silyloxy-5-alkenoic acids undergo efficient and highly stereoselective iodolactonizations leading to the Mevinic analogues and related valerolactones. We have now established that the iodolactonizations of Z- and E-3-silyloxy-5-alkenoic acids (174 and 131) both lead to trans-disubstituted valerolactones, which differ only in the stereochemistry of the iodine substituent (175 and 178).

The possibilities of effecting etherifications of the related Z-3-hydroxy-5- alkenoates (106) are then examined. By simply blocking the carboxylate end of the hydroxy-5-alkenoic acids involved in the above reactions it was found that under iodolactonization conditions a novel iodoetherification-hydroxylation process ensues which leads to 3-hydroxy-2,5-disubstituted tetrahydrofurans of which (182) is an example. These products were essentially single diastereoisomers according to all their spectroscopic data indicating that a well defined transition state must be involved in these cyclizations.

Extensive work was then conducted in probing the mechanism of this reaction which required developing several complementary routes to various homoallylic alcohol precursors. Indeed, results thus generated suggest that the more expected iodotetrahydrofuran (183) is not an intermediate and neither is the plausible epoxide (201). A strong link with hydroxytetrahydrofuran formation and the amount of water present in the reaction was established. That the ester group plays a key role in the cyclization was evident from the observation that its repositioning (135) or removal (137) gave only iodo-diols (204-5 and 221-2) which failed to cyclize further.

Similar cyclizations of the corresponding E-isomers gave iodotetrahydrofurans (199) in excellent yield. In each case, the cyclization was reasonably stereoselective with a modest improvement in yields being obtained in anhydrous solvents. However, under a variety of conditions, these did not lead to hydroxytetrahydrofurans. lodoetherification of simpler Z - and E-3-hydroxy-5-alkenes proceeded efficiently with high levels of stereoselection by a 5-endo-trig process and gave iodotetrahydrofurans, but only when anhydrous acetonitrile was used as solvent. The E-alk-5-en-ols gave a stereoselective reaction and the Z-isomers showed poorer selectivity. In semi-aqueous conditions iodo-diols and not hydroxytetrahydrofurans were obtained. Displacements on the iodotetrahydrofurans with azide (240) and hydroxide (243) equivalents have also been demonstrated in which the inverted products are obtained in good yield as single isomers.

The relevance of all these tetrahydrofurans in Natural Product assembly is then emphasized by a few specific examples.